A number of years ago, the oxygen carrying capacity and lack of toxicity of perfluorinated liquid were reported. Emulsions of fluorocarbon liquids were also used as artificial bloods. In brief, over nearly the last 20 years, considerable work has been accomplished in connection with the use of fluorocarbons and fluorocarbon emulsions as oxygen transfer agents and as artificial bloods. Artificial bloods are now being commercialized, particularly in foreign countries where the requirements for their use and commercialization are not as involved as they are here in the United States. It is inevitable that artificial blood will be commercialized and used throughout the world because of the significant need for such oxygen transport agents and the advantages of such agents over natural blood. U.S. Pat. No. 3,911,138 which issued to Leland C. Clark, Jr. sets forth the various advantages and needs for artificial blood and may be referred to as further background of this invention. In this Clark patent, artificial bloods containing perfluorocyclocarbons were disclosed as useful blood substitutes. Emulsions containing emulsified particles of the perfluorocyclocarbons were also infused intravenously into experimental animals and functioned as oxygen-carbon dioxide carrying agents intravascularly. Furthermore, the perfluorocyclocarbons surprisingly were found to be excreted from the animal body through the tissue, particularly the lungs and skin. The perfluorocyclocarbons disclosed in this Clark patent were referred to as RES-phobic, which indicated that the perfluorocyclocarbons exhibited a unique property of temporary sequestration by the liver or spleen and subsequent elimination by the animal body. It was later disclosed in U.S. Pat. No. 4,105,798 which issued to Leland C. Clark, Jr. et al that certain other perfluoro polycyclic compounds were useful as synthetic blood and perfusion media. The perfluorinated polycyclic compounds disclosed in this patent are known generally as bicyclononanes and adamantanes. Bicyclononanes and adamantanes were found to have a high oxygen solubility, very low body residue, formed very stable emulsions and had a very satisfactory vapor pressure enabling them to be excellent candidates for blood substitutes and perfusion compounds.
Thus, emulsions made from perfluorocyclo compounds such as perfluorodecalin have been found useful as blood substitutes because the cyclic fluorocarbon is transpired by the body through the skin and the lungs. However, in order for these emulsions to be preferred for biological use, they must be freshly prepared because they are not stable. That is, they tend to increase in opacity and the particle size of the fluorocarbon liquid increases rather rapidly with time. This process can be slowed by cooling or even by freezing. Whereas perfluorinated organic amines such as perfluorotributylamine or perfluorotripropylamine will make emulsions having good stability, it is known that such compounds tend to reside in the body, for example the liver or spleen, for considerable periods of time in comparison to the perfluorocyclo compounds such as perfluorodecalin. Recently, therefore, perfluorodecalin and perfluorinated amines such as perfluorotripropylamine have been combined in order to provide an emulsion which has increased stability and which would leave the body at a reasonable rate. Nevertheless, it has been observed that such perfluoroamines as tripropylamine tend to leave the body only very slowly and still such emulsions must also be kept cold or even frozen. Thus, while these compositions attempt to combine perhaps the best properties of both the fluorocarbons employed, namely, perfluorodecalin and perfluorotripropylamine, there are still problems that remain. Nevertheless, these preparations have been employed fairly widely in human beings in life saving procedures and have been proven to be very useful. Therefore, these advances, together with considerable research to date serve to emphasize that highly fluorinated organic compounds in the form of emulsions are very useful in supporting life when used in place of whole blood.
The stability of an emulsion particle in a fluorochemical emulsion has great importance in the sense that the greater the stability, the longer the emulsion can be safely stored before it is used in vivo. In addition, if the emulsion is very stable, it can be stored without refrigeration, a factor of great importance in its possible use as an oxygen transport agent or as an artificial blood for civilian and military purposes, especially in countries where there is little or no refrigeration. Furthermore, a stable emulsion is more predictable from medical standpoints rather than one which tends to deteriorate with time. Normally, after administration to an animal, an emulsion is exposed to body temperatures and this is a factor which may increase its conversion to larger particles. Much remains to be learned about the factors working for and against particle stability in the blood stream and tissues of mammals. While it seems reasonable to suppose that factors which would make for an in vitro stability also make for in vivo stability, there are also special considerations involved in promoting in vivo stability of foreign particles such as perfluorochemical particles. All of the above points to the need for improvements in oxygen transport agents and artificial bloods.